Abstract

In laboratory mice, suppression of growth hormone (GH) signaling by spontaneous mutations or targeted disruption of GH- or IGF1-related genes can lead to an impressive increase of longevity. Hypopituitary Ames dwarf (Prop1 df) and GH receptor knockout (GHRKO) mice live 35-70% longer than their normal littermates. Many phenotypic characteristics of these long-lived mutants resemble findings in genetically normal animals subjected to calorie restriction (CR). Microarray and RT-PCR studies of gene expression suggest that effects of the "longevity assurance genes " (Prop1 df or Ghr-/-) and CR are overlapping but not identical. Subjecting Ames dwarf mice to 30% CR starting at 2 months of age leads to a further significant extension of their average and maximal lifespans. In contrast, identical CR regimen has either no or very little effect (depending on gender) on longevity of GHRKO mice. We suspect that this difference in response is related to the fact that CR improves insulin sensitivity in Ames dwarfs but does not further increase the extreme insulin sensitivity of GHRKO mice. To search for effects of CR associated with extension of longevity, we are studying expression of insulin and IGF1-related genes in the liver, skeletal muscle and heart of normal and GHRKO mice. Results obtained to date suggest that reduced Akt phosphorylation and PPAR beta/delta expression in the liver, reduced JNK1 phosphorylation and increased PGC1alpha expression in the muscle, and increased expression of IGF1 and insulin receptor in the heart are either related to mechanisms of CR action on longevity or represent potential biomarkers of delayed aging.